Impaired memory is an important component of diseases such as Alzheimer's disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to clarify the role of the hippocampus in relational memory. Relational memory refers to the ability to link together the arbitrary or accidental relations among elements of scenes or events. However, there is currently little evidence for relational memory signals in the primate hippocampus at the level of individual neurons or groups of neurons. Monkeys can be tested on some of the very same relational memory tasks as human subjects, and, therefore, neurophysiological studies of the activity of single units and neuronal networks in the monkey hippocampus will be instrumental in identifying the nature of neuronal representations that underlie relational memory. Based on preliminary data, we hypothesize that single neurons and synchronized ensembles of neurons in the hippocampus display modulations in activity that may be used for relational memory. The experiments proposed here will directly test this hypothesis, using multi-electrode recordings of spiking activity and the local field potential (LFP) in the hippocampus of monkeys engaged in a battery of relational memory tasks, adapted from the human literature. We will examine modulations in single-unit firing rates and spike-field neuronal synchronization with respect to relational memory performance encompassing a variety of domains, e.g., spatial, contextual, and temporal. In addition, to assess whether these hippocampal electrophysiological correlates are critical for relational memory processes or whether these processes could also be supported by medial temporal cortical areas in the absence of a functional hippocampus, we will test the effects of restricted lesions of the hippocampus on these same relational memory tasks. The proposed experiments have the following potential outcomes: 1) to determine the changes in neuronal activity in the primate hippocampus that signal the learning of relational associations, 2) to identify neuronal synchronization as a possible mechanism underlying relational memory performance, and 3) to resolve the apparent inconsistencies among human lesion studies regarding the role of the hippocampus in relational memory. PUBLIC HEALTH RELEVANCE: Impaired memory is an important component of diseases such as temporal lobe epilepsy, depression, schizophrenia, and Alzheimer's disease that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to identify neural mechanisms in the hippocampus that may underlie relational memory and to determine whether the hippocampus is necessary for relational memory as distinct from memory for individual items.